Our overall goal is to understand the relationship between sex hormones and cardiovascular disease (CVD) and its risk factors in men who are HIV+ and illicit drugs users (IDU). Several studies have documented premature and accelerated CVD progression in these populations. Although this may be a consequence of the underlying viral mechanisms, anti-retroviral drug therapy, or IDU, we seek to document other mechanisms to explain the increased susceptibility to atherosclerotic disease and metabolic abnormalities in this population. We were one of the first groups to report an increased prevalence of hypogonadism in the HIV-infected men, which was eventually found to result in poor quality of life, decreased lean body mass and increased visceral adiposity. Several population-based studies have now found that low serum testosterone (T) is associated with increased mortality in men. Low serum T may be a risk factor for CVD through increased visceral adiposity (leading to glucose intolerance, diabetes mellitus), inflammation or a more direct effect on the vasculature. The MACS cohort already has in place a substudy to document early atherosclerosis in about 1000 men, measuring carotid intima medial thickness (CIMT) and coronary calcium (CAC) scores. Our overall hypothesis is that HIV+ men with low serum T levels are more likely to have pre-clinical CVD. Our specific aims are: #1: To examine the associations of sex hormones with the severity of atherosclerosis in HIV-infected and IDU men with adjustment for classical atherosclerosis risk factors. Hypothesis #1: Low serum T is independently associated with the presence and severity of pre-clinical atherosclerosis, measured by CAC and CIMT, after adjustment for status and markers of disease stage and duration and components of HIV therapy. #2: To measure the association of sex hormone levels with prevalence, levels and changes in modifiable CV risk factors (inflammatory markers, lipids, lipoproteins, diabetes, and blood pressure), with adjustment for status and markers of disease stage and components of HIV therapy). Hypothesis #2: Low serum T is independently associated with modifiable CVD risk factors (inflammatory markers, lipids, lipoproteins, diabetes, and blood pressure), with adjustment for status and markers of disease stage and duration and components of HIV therapy. To accomplish these specific aims, we will measure total and free T, SHBG, estradiol and LH in men in the MACS, who have been evaluated for pre-clinical atherosclerotic and metabolic disease, using the most up to date assays in collaboration with Dr. Bhasin, Boston. In addition, with this data we have the exciting possibility to explore other avenues of research that are highly likely to be associated with sex hormones, e.g. sexual behaviors, cognitive function and frailty. Low testosterone levels may be a risk factor for cardiovascular disease (CVD) and its risk factors, such as diabetes. Since hormonal abnormalities are common in HIV-infection, we intend to measure sex hormones in a subset of the MACS cohort who have had specialized tests to detect early, pre- clinical CVD. This will lead to a better understanding of the contribution and temporal nature of low sex hormones to metabolic diseases. [unreadable] [unreadable] [unreadable]